The invention relates to benzazole compounds, a process for their preparation and their use as insect-, mite- and tick-repellent compositions.
Repellents and deterrents against insects, mites and ticks have the task of deterring harmful or troublesome arthropods from contacting, stinging, sucking or biting areas that are attractive to them, such as the skin of animals and humans, by means of prior treatment of these areas with such compositions.
In the context of the present invention, arthropods are understood to be in particular insects, mites and ticks. These include insects of the order: Lepidoptera, Coleoptera, Homoptera, Heteroptera, Diptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and Hymenoptera. However, the vermin which may be mentioned in particular are those which trouble humans or animals and carry pathogens, for example flies such as Musca domestics, Musca vetustissima, Musca autumnalis, Fannia canicularis, Sarcophaga carnaria, Lucilia cuprina, Hypoderma bovis, Hypoderma lineatum, Chrysomyia chloropyga, Dermatobia hominis, Cochliomyia hominivorax, Gasterophilus intestinalis, Oestrus ovis, Stomoxys calcitrans, Haematobia irritans and midges (Nematocera), such as Culicidae, Simuliidae, Psychodidae, but also blood-sucking vermin, for example fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), Xenopsylla cheopis, Pulex irritans, Dermatophilus penetrans, lice, such as Damalina ovis, Pediculus humanis, biting flies and horse-flies (Tabanidae), Haematopota spp. such as Haematopota pluvialis, Tabanidea spp. such as Tabanus nigrovittatus, Chrysopsinae spp. such as Chrysops caecutiens, tsetse flies, such as species of Glossinia, biting insects, particularly cockroaches, such as Blattella germanica, Blatta orientalis, Periplaneta americana, mites, such as Dermanyssus gallinae, Sarcoptes scabiei Psoroptes ovis and Psorergates spp. and last but not least ticks. The latter belong to the order Acarina. Known representatives of ticks are, for example, Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros and the like, which preferably infest warm-blooded animals including farm animals, such as cattle, pigs, sheep and goats, poultry such as chickens, turkeys and geese, fur-bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as domestic animals such as cats and dogs, but also humans.
Ticks are responsible world-wide for the transmission and spread of many human and animal diseases. Because of their economic influence, the most important ticks are Boophilus, Rhipicephalus, Ixodes, Hyalomma, Amblyomma and Dermacentor. They are carriers of bacterial, viral, rickettsial and protozoal diseases and cause tick-paralysis and tick-toxicosis. Even a single tick can cause paralysis whereby its saliva penetrates into the host animal during ingestion. Diseases caused by ticks are usually transmitted by ticks, which infest several host animals. Such diseases, for example babesiosis, anaplasmosis, theileriasis and heart water disease, are responsible for the death or impairment of a large number of domestic and farm animals in the entire world. In many countries of temperate climate, Ixodide ticks transmit the agent of the chronically harmful Lyme""s disease from wild animals to humans. Apart from the transmission of disease, the ticks are responsible for great economic losses in livestock production. Losses are not confined to the death of the host animals, but also include damage to the pelts, loss of growth, a reduction in milk production and reduced value of the meat. Although the harmful effects of a tick infestation on animals have been known for years, and enormous progress has been made using tick-control programmes, until now no completely satisfactory methods of controlling or eliminating these parasites have been found, and in addition, ticks have often developed resistance to chemical active ingredients.
The infestation of fleas on domestic animals and pets likewise represents for the owner a problem which has not yet been satisfactorily resolved. Owing to their complex life cycle, none of the known methods for the control of fleas is completely satisfactory, especially as most known methods are basically directed towards the control of adult fleas in the pelt, and leave completely untouched the different juvenile stages of the fleas, which exist not only in the pelt of the animal, but also on the floor, in carpets, in the bedding of the animal, on chairs, in the garden and all other places with which the infested animal comes into contact. Flea treatment is usually expensive and has to be continued over long periods of time. Success usually depends on treating not only the infested animal, e.g. the dog or cat, but at the same time all the locations which the infested animal frequents.
Such a complicated procedure is unnecessary with the present benzazole derivatives. For a particular advantage of the benzazole derivatives under discussion is that they are extremely effective and at the same time of very low toxicity both for the target parasites and for the warm-blooded animals. This is because their activity is based not on the death of the target parasite, but on the parrying defence thereof (as a repellent or as a deterrent), before it sting, bites or in any other way harms the host organism. The presence of the benzazole derivatives being discussed here appears to disturb the parasites in such a way that they suddenly leave the treated environment without biting or stinging, or even do not infest a treated host animal at all. An additional advantage lies in the long-term action, e.g. compared with DEET (N,N-diethyl-m-toluamide), which although very effective, volatilizes rather rapidly and is therefore often difficult to apply. Usage of the present active ingredients is also pleasant because they are almost odourless.
Numerous active ingredients have already been proposed as repellents/deterrents (e.g. K. H. Bxc3xcchel in Chemie der Pflanzenschutzxe2x80x94und Schxc3xa4dlingsbekxc3xa4mpfungsmittel; R. Wegler, Vol. 1, Springer Verlag Berlin, Heidelberg, New York, 1970, pp. 487 ff).
3-Methylbenzoic acid diethylamine (DEET), dimethyl phthalate and 2-ethylhexane-1,3-diol are particularly well-known and have been in use for a long time. Of these, DEET has become particularly important in practice (e.g. R. K. Kocher, R. S. Dixit, C. I. Somaya, Ind. J. Med. Res., 62, 1 (1974)).
Benzazoles are known to be used in various fields:
In Tetrah. Lett., 32(1) 1991, on pages 39-41, substituted benzothiazoles are disclosed as intermediates in the preparation of pharmacophores of anti-viral and anti-tumor alkaloids.
Substituted benzothiazoles are also used as intermediates in the preparation of dyes for light-sensitive silver halide emulsions (e. g. U.S. Pat. No. 5,601,963; DE 25 48 184 A and FR A 2 228 090).
6-Isothiocyano-5-methoxy-2-t-butylbenzothiazole is used to control ruminant liver fluke (U.S. Pat. No. 4,428,957), further isothiocyano-benzothiazoles find their use as bactericides, fungicides and anthelminthics (CH 565 164 A and CH 585 214A).
Further benzazoles are mentioned in e. g. Chem. Ber. 101, 1968, pages 4048-56; Bull. Chem. Soc. Japan, 61(10) 1988, pages 3637-48; Heterocycles, 43(2) 1996, pages 471-4; Indian J. Chem., Apr. 11, 1973, pages 315-7; DE 35 28 032 A; Tetrah. 24, 1968, pages 5569-74; DE 20 53 715 A; DE 24 29 562 A; Chem. Abstr., 53(6) 1959, abstract no. 5246c, col 5246 and WO 98 11095 A.
Certain benzimidazoles are disclosed as additives in pest-repellent combinations (Patent Abstracts of Japan 18(93) (C-1166) 1994 and JP 05 294828 A and 97(11) 1997 and JP 09 175926 A).
In addition, urea derivatives and carboxamides having insect-repelling activity are known (e.g. EP-A-22 653; DE-A-27 56 360; U.S. Pat. Nos. 3,624,204; 4,356,180; EP-B1-0 467 045). A considerable disadvantage of the known repellents/deterrents is partly their relatively short duration of activity (usually only a few hours).
Now, new benzazole derivatives of formula I 
have been found, wherein
R1 and R2 are the same or different and signify hydrogen, hydroxyl, amino, halogen, C1-C6-alkyl, halogen-C1-C6-alkyl, C2-C6-alkenyl, halogen-C2-C6-alkenyl, C3-C6-cycloalkyl, halogen -C3-C6-cycloalkyl C1-C6-alkoxy, halogen-C1-C6-alkoxy, unsubstituted phenyl or phenyl which is optionally substituted by halogen or C1-C6-alkyl; nitro, cyano, isothiocyanato, carboxy, C1-C6-alkoxycarbonyl, halogen-C1-C6-alkoxycarbonyl, C1-C6-alkylcarbamido, which is optionally substituted by phenyl or by unsubstituted or halogen-substituted phenoxy; PhNH(CO)NH, C1-C6-alkylsulphonyl, halogen-C1-C6-alkylsulphonyl, unsubstituted or optionally halogen-substituted benzoyl; unsubstituted or optionally halogen-substituted phenylthionyl or phenylsulphonyl;
R3 and R4, independently of one another, are hydrogen, R1, R2 or together are a CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 bridge;
X is NR5, O or S;
Y is N, CR6 or Cxe2x95x90O;
R6 is hydrogen, hydroxyl, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxy, cyano, 2-di(C1-C6alkyd)aminoethenyl, (C1-C6-alkyl)NHC(xe2x95x90S)NHCH2, phenyl, thiazolyl, phenylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkoxy; C1-C6-alkyl-carbamido, C1-C6-alkoxycarbamido, guanidyl, amino, hydroxyl-C2-C6-alkylamino or phenylsulphonylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkyl;
Z is N or CR7; and
R7 is hydrogen or C1-C6-alkyl,
which are eminently suitable for long-term repellent/deterrent action against ectoparasites on warm-blooded animals. The repellent/deterrent action is considerably better than that of the repellents/deterrents known from the prior art. The expression ectoparasite as used here has the normal meaning according to the prior art and includes fleas, ticks, lice, mosquitos, horse flies, tsetse flies and other biting flies, especially ticks.
The general terms used hereinbefore and hereinafter, if not defined to the contrary, have the meanings given below.
Halogenxe2x80x94as a group per se and as structural element of other groups and compounds such as halogen-alkyl, halogen-cycloalkyl and halogen-alkenylxe2x80x94is fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine, in particular fluorine or chlorine.
Halogen-substituted carbon-containing groups, such as halogen-alkyl, halogen-cycloalkyl, halogen-alkenyl, halogen-alkoxy or halogen-alkoxycarbonyl, may be partially halogenated or perhalogenated, whereby in the case of multiple halogenation, the halogen substituents may be identical or different. Examples of halogen-alkylxe2x80x94as a group per se and as structural element of other groups and compounds such as halogen-cycloalkyl, halogen-alkenyl, halogen-alkoxy or halogen-alkoxycarbonyl,xe2x80x94are methyl which is mono- to trisubstituted by fluorine, chlorine and/or bromine, such as CHF2 or CF3; ethyl which is mono- to pentasubstituted by fluorine, chlorine and/or bromine, such as CH2CF3, CF2CF3, CF2CCl3, CF2CHCl2, CF2CHF2, CF2CFCl2, CF2CHBr2, CF2CHClF, CF2CHBrF or CClFCHClF; propyl or isopropyl, mono- to heptasubstituted by fluorine, chlorine and/or bromine, such as CH2CHBrCH2Br, CF2CHFCF3, CH2CF2CF3 or CH(CF3)2; and butyl or one of its isomers, mono- to nonasubstituted by fluorine, chlorine and/or bromine, such as CF(CF3)CHFCF3 or CH2(CF2)2CF3; pentyl or one of its isomers substituted one to eleven times by fluorine, chlorine and/or bromine, such as CF(CF3)(CHF)2CF3 or CH2(CF2)3CF3; and hexyl or one of its isomers substituted one to thirteen times by fluorine, chlorine and/or bromine, such as (CH2)4CHBrCH2Br, CF2(CHF)4CF3, CH2(CF2)4CF3 or C(CF3)2(CHF)2CF3.
If not defined to the contrary, carbon-containing groups and compounds contain 1 to 6, preferably 1 to 4, especially 1 or 2, carbon atoms.
C3-C6-cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alkylxe2x80x94as a group per se and as structural element of other groups and compounds such as alkoxy, halogen-alkyl or halogen-alkoxyxe2x80x94is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question, either straight-chained or branched, and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl or pentyl, hexyl, or one of the respective isomers thereof. Preferred alkyl groups R1 are C1-C3-alkyl groups, especially C1-C2-alkyl groups.
Alkenyl contains one or more, preferably no more than two, unsaturated carbon-carbon bonds. Examples which may be mentioned are vinyl, allyl, methallyl, prop-1-en-1-yl, 2-methyl-prop-1-en-1-yl and but-2-en-1-yl.
The compounds which are preferred within the scope of the invention are
(1) compounds of formula I, wherein
R1 and R2 are identical or different and are hydrogen, hydroxyl, amino, halogen, C1-C6-alkyl, halogen-C1-C6-alkyl, C1-C6-alkoxy, nitro, cyano, isothiocyanato, carboxy, C1-C6-alkoxy -carbonyl, C1-C6-alkylcarbamido which is optionally substituted by phenyl or by unsubstituted or halogen-substituted phenoxy; PhNH(CO)NH, C1-C6-alkylsulphonyl, halogen-C1-C6-alkylsulphonyl, benzoyl, phenylthionyl or phenylsulphonyl;
(2) compounds of formula I, wherein
X is NH O or S;
(3) compounds of formula I, wherein
Y is CR6 or Cxe2x95x90O; and
R6 is hydrogen, C1-C6-alkyl, C1-C6-alkylcarbonyl, cyano, 2-di(C1-C6-alkyl)aminoethenyl, phenyl, thiazolyl, phenylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkoxy; C1-C6-alkylcarbamido, C1-C6-alkoxycarbamido, guanidiyl, amino, hydroxy-C2-C6-alkylamino or phenylsulphonylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkyl;
(4) compounds of formula I, wherein
Z is N;
(5) compounds of formula I, wherein
R1 and R2 are identical or different and are hydrogen, hydroxyl, amino, halogen, C1-C2-alkyl, halogen-C1-C2-alkyl, C1-C2-alkoxy, nitro, cyano, isothiocyanato, carboxy, ethoxycarbonyl, C1-C6-alkylcarbamido which is optionally substituted by phenyl or by unsubstituted or halogen-substituted phenoxy; PhNH(CO)NH, C1-C6-alkylsulphonyl, halogen-C1-C6-alkylsulphonyl, benzoyl, phenylthionyl or phenylsulphonyl;
R3 and R4 are H or together are a CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 bridge;
X is O or S;
Y is CR6 or Cxe2x95x90O;
R6 is hydrogen, C1-C6-alkyl, C1-C6-alkylcarbonyl, cyano, 2-di(C1-C6-alkyl)aminoethenyl, phenyl, thiazolyl, phenylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkoxy; C1-C6-alkylcarbamido, C1-C6-alkoxycarbamido, guanidiyl, amino, hydroxy-C2-C6-alkylamino or phenylsulphonylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkyl; and
Z is N;
(6) compounds of formula I, wherein
R1 and R2 are identical or different and are hydrogen, amino, halogen, C1-C2-alkoxy, isothiocyanato, C1-C6-alkylsulphonyl, halogen-C1-C6-alkylsulphonyl or benzoyl;
R3 and R4 are H or together are a CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 bridge;
X is S;
Y is CR6 or Cxe2x95x90O;
R6 is C1-C6-alkyl, C1-C6-alkylcarbonyl or 2-di(C1-C6-alkyl)aminoethenyl; and
Z is N;
The following compounds of formula I are those which are preferred within the scope of the invention:
X is O or S;
Y is CR6 or Cxe2x95x90O;
R6 is hydrogen, C1-C6-alkyl, C1-C6-alkylcarbonyl, cyano, 2-di(C1-C6-alkyl)aminoethenyl, phenyl, thiazolyl, phenylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkoxy; C1-C6-alkylcarbamido, C1-C6-alkoxycarbamido, guanidiyl, amino, hydroxy-C2-C6-alkylamino or phenylsulphonylamino, whereby the phenyl group is unsubstituted or optionally substituted by C1-C6-alkyl; and
Z is N;
(6) compounds of formula I, wherein
R1 and R2 are identical or different and are hydrogen, amino, halogen, C1-C2-alkoxy, isothiocyanato, C1-C6-alkylsulphonyl, halogen-C1-C6-alkylsulphonyl or benzoyl;
R3 and R4 are H or together are a CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 bridge;
X is S;
Y is CR6 or Cxe2x95x90O;
R6 is C1-C6-alkyl, C1-C6-alkylcarbonyl or 2-di(C1-C6-alkyl)aminoethenyl; and
Z is N;
The following compounds of formula I are those which are preferred within the scope of the invention:
2-ethyl-5-methoxy-6-isothiocyanatobenzothiazole,
2-t-butyl-5-methoxy-6-isothiocyanatobenzothiazole,
5-amino-2-methylbenzothiazole,
2-(2-dimethylaminoethenyl)-benzothiazole,
2-propionylbenzothiazole,
4-chloro-2-methylbenzothiazole,
5,6-dimethoxy-2-methylbenzothiazole,
2-methylnaphtho[1,2-d]thiazole,
6-methoxy-2-methylbenzothiazole,
5-trifluoromethylsulphonyl-2-methylbenzothiazole,
6-benzoyl-(2H)-benzoxazolone and
3-acetyl-6-fluoro-(2H)-benzoxazolone;
especially
5-amino-2-methylbenzothiazole and
5,6-dimethoxy-2-methylbenzothiazole.
The invention includes all the compounds of formula I, provided that they are new. General processes for the preparation of compounds of formula I are known. It has been found that benzazole derivatives of formula I are obtained whereby, for example,
a) in order to produce compounds of formula I, wherein Y and Z are N, and X, R1, R2, R3 and R4 have the significances given in formula I, a compound of formula 
xe2x80x83which is known or may be produced by known processes, and wherein X, Z, R1, R2, R3 and R4 have the significances given in formula I, is reacted with NaNO2 in an aqueous solution containing a mineral acid, or
b) in order to produce compounds of formula I, wherein Y is N, Z is CR7, and X, R1, R2, R3 and R4 have the significances given in formula I, a compound of formula 
xe2x80x83which is known or may be produced by known processes, and wherein R1, R2, R3, R4 and R7 have the significances given in formula I, is reacted with NaNO2 in an aqueous solution containing a mineral acid, and the resultant intermediate, if necessary after interim isolation, is reduced with a reduction agent such as SnCl2, sodium dithionite or zinc dust in water, or
c) in order to produce compounds of formula I, wherein Y is CR6, Z is N, and X, R1, R2, R3 and R4 have the significances given in formula I, a compound of formula II, wherein X, Z, R1, R2, R3 and R4 have the significances given in formula I, is reacted with a compound of formula QCOR6, wherein Q is hydroxyl, C1-C2-alkoxy or halogen, and R6 has the significance given in formula I, or
d) in order to produce compounds of formula I, wherein Y is CR6, Z is CR7, and X, R1, R2, R3 and R4 have the significances given in formula I, a compound of formula 
xe2x80x83which is known or may be produced by known processes, and wherein X, R1, R2, R3 and R4 have the significances given in formula I, is reacted with a compound of formula QC(R6)C(xe2x95x90O)R7, wherein Q is hydroxyl or halogen, and R6 and R7 have the significances given in formula I, or
e) in order to produce compounds of formula I, wherein Y is COH, Z is N, and X, R1, R2, R3 and R4 have the significances given in formula I, a compound of formula II is reacted with phosgene or with a carbonic acid dialkylester, or
f) in order to produce compounds of formula I, wherein X is O or S, Y is N, Z is CR7 and R1, R2, R3 and R4 have the significances given in formula I, it is reacted with ClNH2,
and if desired, a compound of formula I which is obtainable by this process or in another way, or a tautomer thereof, may be converted into another compound of formula I or a tautomer thereof, a mixture of isomers which is obtainable by this process is separated and the desired isomer isolated.
In the process of the present invention, the starting materials and intermediates used are preferably those which lead to the compounds I that were initially portrayed as especially valuable.
Starting materials and intermediates, which are new and are used according to the invention for the preparation of compounds I, as well as their usage and process for the preparation thereof, similarly form an object of the invention.
Although the present benzazole derivatives can of course be mixed with other substances having the same sphere of activity or with parasiticides or with other activity-improving substances to achieve further improved or longer-lasting action, and then applied, in contrast to many compounds of the prior art, this is totally unnecessary, as they already combine all the advantageous properties.
If the parasite is not only to be kept at bay, but also killed, of course this can be achieved by adding appropriate insecticides and/or acaricides. In practice, however, this is unnecessary in most cases.
The present benzazole derivatives are preferably used in diluted form. Normally, they are brought to the final application form by using appropriate formulation excipients, whereby the preparations of the formulations to be applied are produced in known manner by mixing or diluting the active ingredients according to the invention with solvents (e.g. xylene, chlorobenzenes, paraffins, methanol, isopropanol, water), carrier materials (e.g. kaolins, clay, talc, chalk, highly dispersed silicic acid, silicates), emulsifiers (e.g. polyoxyethylenexe2x80x94fatty acid esters, polyoxyethylene fat alcohol ether, alkyl sulphonates, aryl sulphonates) and dispersing agents (e.g. lignin, waste sulphite lye, methyl cellulose).
Since they are in many instances applied to warm-blooded animals and of course come into contact with the skin, suitable formulation excipients are the excipients and administration forms that are known in cosmetics. They may be administered in the form of solutions, emulsions, ointments, creams, pastes, powders, sprays, etc. The preparations generally contain between 0.1 and 95% by weight of active ingredient, preferably between 0.5 and 90%.
For administration to farm animals or pets, the so-called xe2x80x98pour-onxe2x80x99 or xe2x80x98spot-onxe2x80x99 formulations are especially suitable; these liquid or semi-liquid formulations have the advantage that they only have to be applied to a small area of the pelt or plumage, and, thanks to the proportion of spreading oils or other spreading additives, they disperse by themselves over the whole pelt or plumage, without further support, and become active over the whole area.
Of course, inanimate objects, for example human clothing or dog and cat baskets, may be treated with said formulations and thus protected from parasite infestation.
In order to control cockroaches, their locus, usually cracks in the walls, furniture, etc., can be sprayed or powdered.
For the application on humans, a pleasant-smelling essence, e.g. a perfume, can be added to make the application more attractive.